Compositions and Methods for Treatment and Prevention of Pyrexia in Horses

ABSTRACT

Methods for treating and preventing pyrexia and other diseases in equines such as horses involving administering an oral pharmaceutical formulation containing metamizole are disclosed.

This application is a divisional of U.S. patent application Ser. No.15/554,568, filed Aug. 30, 2017, which is a U.S. national stage ofInternational Application No. PCT/US2016/020463, filed Mar. 2, 2016,which claims the benefit of priority to U.S. Provisional Application No.62/127,401, filed Mar. 3, 2015, which is incorporated by referenceherein in its entirety for any purpose.

FIELD

The present disclosure provides new pharmaceutical formulations,delivery and treatment methods for administering metamizole and itspharmaceutically acceptable salts to non-human animals, particularlyequines, for therapeutic purposes, including but not limited to thetreatment and prevention of pyrexia. The present disclosure alsoprovides a process for the preparation of the new pharmaceuticalformulations.

BACKGROUND

Pyrexia (fever) is common to all mammals, including equines such ashorses. Pyrexia is an elevation in core body temperature above thenormal range due to an increase in the temperature regulatory set-point.Pyrexia can be caused by many medical conditions ranging fromnon-serious to potentially serious and even life threatening. Theseinclude viral, bacterial, and parasitic infections, such as equineencephalomyelitis, equine influenza, equine herpes virus, West Nilevirus, strangles, and Potomac horse fever. Physical trauma and stresscan also cause a fever in a horse. While a fever can be a useful defensemechanism, since the body's immune response can be strengthened athigher temperatures, very high body temperatures, particularly forprolonged periods of time, can pose significant health risks to thepatient. In the setting of animal and human healthcare, it often becomesnecessary to reduce a patient's temperature to a safer range (e.g.,treat the patient's fever) by medical intervention. Some of the mostcommon causes of illness in horses are febrile diseases, such asrespiratory infections, certain forms of colic, post-vaccinationreactions, and tick- and mosquito-borne infections).

The treatment of pyrexia in horses and foals by parenteraladministration of the nonsteroidal anti-inflammatory drug (NSAID)metamizole is known in the art. Metamizole products are marketed in somecountries under the generic name dipyrone and a variety of brand namesincluding, but not limited to Vetalgin® as an antipyretic, analgesic,and anti-inflammatory agent. Currently available veterinary formulationsof metamizole require parenteral (i.e., intramuscular, intravenous (IV),or subcutaneous) administration, with IV administration being the usualroute. The oral formulations of metamizole available in the veterinarymarket for dogs are not suitable for administration to horses due to avariety of factors including dose. Obtaining an oral dosage form ofmetamizole of sufficiently high concentration to treat a large animalsuch as a horse is itself technically challenging, but to further do so(i) in an oral format that facilitates the horses actually ingesting thedrug as opposed to expelling it from the mouth prior to ingestion, and(ii) in an oral format that is stable at the temperatures typicallyfound in a barn environment, is even more so.

Parenteral administration of metamizole in horses presents manydifficulties, however, and there is a need for simpler methods fortreating pyrexia. Horses have large jugular veins that, when healthy,are simple to access. However, other peripheral vessels are much morechallenging. Access to jugular veins can be limited for numerousreasons, including but not limited to thrombosis, poor temperament, andlocalized dermal disease. Once the jugular veins are inaccessible,intravenous administration of medication to a horse is extremelychallenging. Moreover, in some instances, an unintended peri-vascularadministration of metamizole to an equine may result in adverse effects,including, but not limited to, thrombophlebitis. This is true of NSAIDs,like metamizole, generally. Further complications can arise due to, inmany instances, medications being administered to horses bynon-veterinary personnel. These individuals often lack the training andexperience to administer parenteral medications safely. Additionally,many medications are administered repeatedly or chronically, which maylead to thrombosis of the vein. Finally, the equine patient may alsodevelop evasive behaviors, so repeat parenteral administration of anymedication can be challenging for that reason alone.

For these and other reasons, there exists an unmet need for veterinaryformulations of metamizole suitable for oral administration to equinesto treat pyrexia that avoid difficulties commonly known and experiencedwith the currently available parenteral formulations. There furtherexists an unmet need for oral veterinary formulations of metamizole thatcan be easily and readily administered to a horse, even by unskilledcaretakers who are not veterinarians. Such formulations and methods forusing and administering them are provided by the present disclosure.

SUMMARY

The present disclosure provides methods for the prevention of pyrexiaand other diseases in horses by oral administration of a therapeuticallyeffective amount of metamizole. Typically, the therapeutically effectiveamount for an adult horse will be a unit dose of the therapeuticformulation sufficient to administer an oral dose of metamizole in therange of 10-60 mg of metamizole per kg of subject weight, i.e.,typically about 25-50 mg/kg or 30-40 mg/kg, and so for the typical 350kg to 1000 kg adult mare, a typical therapeutically effective (single)dose administered at, e.g., 30 mg/kg would be in the range 10.5 g to 30g. For a foal, the therapeutically effective amount will be a unit doseof the therapeutic formulation sufficient to administer an oral dose ofmetamizole in the range of 10-50 mg of metamizole per kg of subjectweight, i.e., typically about 15-40 mg/kg, and so for the typical foal(for example, weighing approximately 35-100 kg), a typicaltherapeutically effective (single) dose administered at, e.g., 20 mg/kgwould be in the range of 700 to 2000 mg. The present disclosure alsoprovides oral formulations of metamizole. In these oral formulations,the concentration of metamizole ranges from about 200 to 750 mg/ml,making the dose of a typical formulation, i.e., where the metamizole ispresent at 500 mg/ml, for the typical adult mare in the range of 20 to100 ml, which can easily be administered using for example a syringe fordepositing the dose in the horse's mouth. The formulations of thepresent disclosure include, but are not limited to, materials viscousenough to remain in the mouth after administration, and include pasteand gel formulations.

In some embodiments, a pharmaceutical composition comprising 200 mg/mlto 750 mg/ml, or 250 mg/ml to 750 mg/ml, or 400 mg/ml to 600 mg/ml,metamizole is provided, wherein the pharmaceutical composition is fororal administration to equines. In some embodiments, the pharmaceuticalcomposition is a gel or paste. In some embodiments, said gel or pastecomprises hydroxypropylcellulose, for example, at a concentration of 10to 50 mg/ml, or 10 to 40 mg/ml, or 10 to 30 mg/ml, or 15 to 25 mg/ml. Insome embodiments, said gel or paste comprises at least one paraben. Insome embodiments, said gel or paste comprises methyl paraben and/orpropyl paraben, or methyl paraben and propyl paraben. In someembodiments, the total parabens are present at a concentration of 0.1 to5 mg/ml, or 0.5 to 5 mg/ml, or 1 to 3 mg/ml.

In some embodiments, a pharmaceutical composition for oraladministration of metamizole to equines is provided, wherein thepharmaceutical composition comprises at least one polymeric excipient.In some embodiments, the at least one polymeric excipient is selectedfrom albumin, acacia, alginic acid (or alginate salts, e.g. sodiumalginate), bentonite, carbomers, carboxymethylcellulose, carrageenan,cellusoses, cellulose ethers, chitosan derivatives, dextran, divinylether-maleic anhydride (DIVEMA), dydroxyethylcellulose, ethylcellulose,gelatin, guar gum, hyaluronic acid (HA), hydroxy ethylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose,N-(2-Hydroxypropyl) methacrylamide (HPMA), magnesium aluminum silicate,methylcellulose, pectins, polyacrylamides, polyacrylic acid (PAA),polyethylene glycol (PEG) and PEG conjugates, polyethylene oxides,polyoxamers, polyoxazoline, polyphosphates, polyphosphazenes, polyvinylalcohol (PVA), polyvinyl pyrrolidone (PVP), polyvinyl pyrrolidone-vinylacetate (PVP-VA), starch or starch based derivatives, tragacanth, andxanthan gum. In some embodiments, the pharmaceutical composition fororal administration of metamizole to equines comprises xanthan gum. Insome embodiments, the xanthan gum is present at a concentration of 1mg/ml to 50 mg/ml, or 1 mg/ml to 40 mg/ml, or 1 mg/ml to 30 mg/ml, or 1mg/ml to 20 mg/ml, or 5 mg/ml to 20 mg/ml, or 5 mg/ml to 15 mg/ml.

In some embodiments, a pharmaceutical composition for oraladministration of metamizole to equines is provided, wherein thepharmaceutical composition comprises at least one preservative agent. Insome embodiments, the preservative agent is selected from alcohol,benzyl alcohol, bronopol, chlorbutol, chlorocreson, a paraben such as,without limitation, butyl, methyl or propyl paraben, phenol,phenylethanol, sodium benzoate, potassium sorbate, sorbic acid,glycerin, and propylene glycol. In some embodiments, the pharmaceuticalcomposition for oral administration of metamizole to equines comprisespropylene glycol. In some embodiments, the propylene glycol is presentat a concentration of 10 mg/ml to 500 mg/ml, or 10 mg/ml to 300 mg/ml,or 50 mg/ml to 300 mg/ml, or 50 mg/ml to 200 mg/ml, or 50 mg/ml to 150mg/ml.

In some embodiments, a gel or paste comprising 200 mg/ml to 750 mg/ml,or 250 mg/ml to 750 mg/ml, or 400 mg/ml to 600 mg/ml metamizole isprovided, wherein the gel or paste comprises xanthan gum, for example,at a concentration of 1 mg/ml to 50 mg/ml, or 1 mg/ml to 40 mg/ml, or 1mg/ml to 30 mg/ml, or 1 mg/ml to 20 mg/ml, or 5 mg/ml to 20 mg/ml, or 5mg/ml to 15 mg/ml. In some embodiments, the gel or paste comprisespropylene glycol, for example, at a concentration of 10 mg/ml to 500mg/ml, or 10 mg/ml to 300 mg/ml, or 50 mg/ml to 300 mg/ml, or 50 mg/mlto 200 mg/ml, or 50 mg/ml to 150 mg/ml.

In some embodiments, the pharmaceutical composition provided hereincomprises 500 mg/mL metamizole sodium monohydrate, 10 mg/ml xanthan gum,and 100 mg/ml propylene glycol, in an aqueous solution.

In various embodiments, methods of treating an equine with pyrexia areprovided, said method comprising orally administering a therapeuticallyeffective dose of metamizole to said equine. In some embodiments, saiddose is in the range of 25 mg metamizole per kg of equine subject weight(mg/kg) to 40 mg/kg, or in the range of 30 mg metamizole per kg ofequine subject weight (mg/kg) to 35 mg/kg. In some embodiments,following administration of the oral metamizole, the equine'stemperature is reduced by at least 1° C. or at least 1.5° C. or at least2° C. six hours after administration of metamizole. In some embodiments,following administration of the oral metamizole, the equine'stemperature is reduced by at least 1° C. or at least 1.5° C. or at least2° C. six hours after administration of the first dose of metamizole. Invarious embodiments, the temperature is rectal temperature.

Thus, in some embodiments, the present disclosure provides various oralformulations and methods of using such formulations in treatments forcontrolling fever and other diseases in horses. The methods includeadministering e.g., once, several times, or periodically, atherapeutically effective amount of metamizole by oral administration toa horse. In certain embodiments, the oral formulation is a formulationdescribed herein. The present disclosure further includes, in variousembodiments, various veterinary oral formulations of metamizole, as wellas various methods of treatment.

One aim of the present disclosure was a pharmaceutical formulation ofmetamizole that could be easily administered in a therapeuticallyeffective amount to an equine. Example 1, below, demonstrates how thisobject of the disclosure was achieved using simple aqueous formulationsof metamizole administered orally to horses. Because veterinarians andcaretakers generally prefer more viscous formulations of orallyadministered medications intended for use in horses, however, thepresent disclosure also provides oral formulations comprising one ormore gels or other thickening agents. In one important aspect, apharmaceutical gel or paste formulation is provided comprising atherapeutically effective amount of metamizole and having a viscositysuch that is can be easily drawn into a syringe and, after the desireddose is administered by deposition in a horse's mouth, will remain therelong enough for the desired dose to be consumed.

SUMMARY OF THE DRAWINGS

FIG. 1 is a chart showing the results of metamizole bioavailability fororal and intravenous dosage forms that have been administered to horsesat a dose of 30 mg/kg, as described in Example 1.

DETAILED DESCRIPTION

In one aspect, the present disclosure provides a pharmaceuticalformulation of metamizole that is a gel or paste or other pharmaceuticalformulation intended for oral administration. This aspect of thedisclosure arose in part from the surprising discovery that metamizolecould be effectively dosed orally, in combination with overcoming thechallenges associated with successfully administering therapeuticallyeffective levels of metamizole orally to a horse. These challengesincluded developing a gel or paste formulation, as a solution or otherliquid formulation of insufficient viscosity would be at risk of lossafter administration, due to the nature of the horse's mouth and throat.The present disclosure provides novel gel and paste formulations ofmetamizole that have sufficiently high viscosity to remain in placeafter oral administration and to deliver therapeutically effectivedoses. To facilitate description of the invention and betterappreciation of its advantages, the following definitions are provided.

Definitions

Unless defined otherwise below, all technical and scientific terms usedherein have the same meaning as is commonly understood by one ofordinary skill in the art to which this disclosure pertains.

The terms “a” and “an” and “the” and similar referents as used hereinrefer to both the singular and the plural, unless otherwise indicatedherein or clearly contradicted by context.

The term “about” as used herein refers to greater or lesser than thevalue or range of values stated by 1/10 of the stated values, but is notintended to limit any value or range of values to only this broaderdefinition. For instance, a value of “about 30%” means a value ofbetween 27% and 33%. Each value or range of values preceded by the term“about” is also intended to encompass the embodiment of the statedabsolute value or range of values. Recitation of ranges of values hereinare merely intended to serve as a shorthand method of referringindividually to each separate value inclusively falling within therange, unless otherwise indicated herein, and each separate value isincorporated into the specification as if it were individually recitedherein.

The phrase “bulking agent” refers to an excipient suitable for use in apharmaceutical formulation that is inert and simply provides the productwith more mass than it would have otherwise. Suitable bulking agents foruse in the pharmaceutical formulations include, without limitation,polyethylene glycol (PEG), such as PEG 400 and PEG 3350.

The phrase “colloidal dispersion” refers to a material in whichparticles of colloidal dimension (i.e., typically between 1 nm and 1 μm)are distributed uniformly throughout a liquid.

The term “cream” refers to a type of emulsion, comprising at least twoimmiscible liquid phases, one dispersed in the form of drops or dropletswithin the other. Creams typically are intended for external applicationto the skin or mucous membranes.

The term “gel” as used herein refers to a material that is safe for oraladministration to an equine such as a horse that is a semisolid dosageform that contains a gelling agent to provide stiffness to a solution ora colloidal dispersion. A gel may contain suspended particles.

The term “metamizole” (also known as “dipyrone”) as used herein refersto[(2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazol-4-yl)methylamino]methanesulfonic acid and its pharmaceutically acceptable salts.Metamizole is available commercially (e.g., BOC Sciences) and generallyhas the structure shown in Formula I:

Any reference to metamizole herein impliedly refers to anypharmaceutically acceptable salt, polymorph, crystal, or pro-drug formthereof. Metamizole and metamizole sodium and metamizole sodiummonohydrate are known compounds in the art and methods for theirpreparation may be found in the literature. An exemplarypharmaceutically acceptable salt of metamizole is the sodium salt havingthe structure in Formula II:

Metamizole sodium monohydrate is metamizole sodium with a single watermolecule associated with the metamizole sodium. In various embodimentsprovided herein, the stable active metabolite of metamizole,4-methylaminoantipyrine (4-MAA), may be used in place of metamizole inthe pharmaceutical compositions provided herein.

The term “ointment” refers to a pharmaceutical formulation that is asemisolid preparation intended for external application to the skin ormucous membranes and includes compositions derived from four “ointmentbases,” which are hydrocarbon bases, absorption bases, water-removablebases, and water-soluble bases. The Merck Veterinary Manual defines“ointment” as a greasy, semi-solid preparation that contains dissolvedor dispersed drug. Ointment bases include hydrocarbons, vegetable oils,silicones, absorption bases consisting of a mixture of hydrocarbons andlanolin, emulsifying bases consisting of a mixture of hydrocarbons andan emulsifying agent, and water-soluble bases. Ointment bases influencetopical drug bioavailability by (i) their occlusive properties thathydrate the stratum corneum, which can enhance drug flux across theskin; and (ii) their properties that affect drug dissolution within theointment and drug partitioning from the ointment to the skin.

The term “paste” refers to a pharmaceutical formulation that is asemisolid preparation of stiff consistency intended for externalapplication to the skin, oral cavity, or mucous membranes and is asemisolid dosage form containing a large proportion (20-50%) of solidsfinely dispersed in a fatty vehicle.

The phrase “pharmaceutical formulation” refers to a composition intendedfor therapeutic use that is safe and effective for its intended use. Aformulation safe and effective for one type of use, such as topicalapplication, may not be safe or effective for another type of use, suchas IV administration. Thus, a “pharmaceutical formulation for topicaladministration”, for example, excludes any type of pharmaceuticalformulation that would not be safe or effective for its intended use.

The term “preservative” refers to an excipient suitable for use in apharmaceutical formulation, such as an ointment, that functions tomaintain the drug in a desired physical state. A preservative may haveanti-microbial or anti-oxidant properties or may otherwise serve toprotect the drug, e.g., from exposure to light or air. Suitablepreservatives include parabens such as, without limitation, butyl,methyl or propyl paraben; sodium metabisulfate; potassium sorbate;sorbic acid; and butylated hydroxytoluene (BHT).

The term “pyrexia” refers to an elevation in body temperature (i.e., afever) that is believed by a physician or veterinarian to requiremedical intervention to lower, e.g., to a safe set-point.

The term “semisolid” refers to a material that is not pourable; it doesnot flow or conform to its container at room temperature. It does notflow at low shear stress and generally exhibits plastic flow behavior.

The term “solubilizer” refers to an excipient suitable for use in apharmaceutical formulation, such as an ointment, that facilitatesdissolution of a drug into another substance. Suitable solubilizers foruse in the pharmaceutical formulations provided herein include, withoutlimitation, DGME, Labrasol®, and oleyl alcohol.

The term “solution” refers to a homogenous liquid preparation thatcontains one or more chemical substances dissolved in one or a mixtureof miscible solvents.

The phrase “therapeutically effective dose” refers to that amount of adrug (an “active pharmaceutical ingredient” or “API”) that isadministered simultaneously or contemporaneously in one administration(multiple unit dose forms, i.e., pills, tablets, capsules, injections,liquids, pastes can be administered in one administration) to achieve adesired therapeutic outcome, even if multiple administrations over timeare administered in the course of therapy.

In various embodiments, the metamizole is used in a pharmaceuticalformulation for oral administration to a horse to prevent or treatpyrexia. In various preferred embodiments, the metamizole is orallyadministered in the form of a gel. A therapeutically effective dose ofmetamizole for practice of the methods provided herein is in the rangeof 25 mg to 40 mg metamizole/per kg weight of animal (mg/kg)/per dose.Typically, the therapeutically effective dose is administered only once,or no more than a few times, daily, and daily administration continuesfor several days or longer, but single day treatments can be effectivein some animals for some purposes. Generally, however, treatment willcontinue on consecutive days for several days to a week, or longer. Thedose may be adjusted using kg of weight of the animal to be treated. Insome embodiments, oral administration with a gel formulation providedherein is continued for 2, 3, 5, 7, or more consecutive days.

The phrases “thickening agent” and “gelling agent” as used herein refersto any pharmaceutically acceptable substance that can increase theviscosity of a liquid without substantially changing its other desiredproperties.

In some embodiments, the present disclosure provides a pharmaceuticalformulation that is a gel, paste or other suitable semi-solid form thatcan be placed in the mouth of the horse, i.e., with an applicator suchas a syringe or spatula, to provide for oral ingestion of theformulation when the animal swallows the material. In preferredembodiments, however, the formulation is a gel that is placed in theanimal's mouth so that it is consumed orally. Thus, in some embodimentsthe present disclosure provides a pharmaceutical formulation that is gelor other suitable semi-solid form that can be orally administered.

The present disclosure provides new oral pharmaceutical formulationscomprising metamizole. In some embodiments, the present disclosureprovides a pharmaceutical formulation of metamizole for oraladministration comprising a therapeutically effective amount ofmetamizole, such as metamizole sodium or metamizole sodium monohydrate,and a thickening agent, and optionally a flavoring. In some embodiments,the thickening agent is a polymer or a monomer and a gelling agent or anadmixture of any and all.

In some embodiments of the present disclosure, the pharmaceuticalcomposition contains metamizole at a concentration sufficiently high toenable dosing at 25-40 mg/kg, i.e., concentrations in the range of about200 mg/ml to 750 mg/ml, or 250 mg/ml to 750 mg/ml. Typically, theadministered dose will be in the range of from about 10 to 50 mg/kg, or10 to 40 mg/kg, or 20 to 50 mg/kg, or 20 to 40 mg/kg, or 10 mg/kg to 35mg/kg, or 10 to 30 mg/kg, or 15 to 35 mg/kg, or 15 to 30 mg/kg. In someembodiments of the present disclosure the pharmaceutical compositioncontains metamizole in a range of about 25% w/w to 50% w/w.

In some embodiments, the therapeutically effective unit dose has avolume of from about 10 to 100 ml, or about 10 to 75 ml, or about 10 to50 ml, and preferably of 20 ml to 30 ml.

In some embodiments, the therapeutically effective dose is 30 mg/kg andthe concentration of metamizole in the oral dose formulation is 500mg/ml.

The oral formulations provided herein generally have a viscosity higherthan that of, for example and without limitation, the Vetalgin(Intervet) metamizole product for IV administration, which, as shown inthe examples can be orally administered in accordance with the presentdisclosure to treat pyrexia. The desired viscosity is in the range ofthat of a semisolid, i.e., a gel or paste, which enables theadministrator of the drug to place a therapeutically effective dose inthe horse's mouth with confidence that it will be consumed rather thanwash out of the horse's mouth as a solution would.

The desired viscosity is at least about 200 centipoise (cps) to 30,000cps, of 200 cps to 20,000 cps, or 500 cps to 10,000 cps, or 1,000 cps to7,000 cps, at 25° C. In some embodiments, the pharmaceutical compositioncomprises a thickening agent in a concentration sufficient to achieve afinal viscosity of greater than 500 cps and less than 10,000 cps at 25°C.

This viscosity may be achieved by using a variety of pharmaceuticallyacceptable polymeric excipients or other thickening agents and/orgelling agents, illustrative examples of which are described below, suchthat the novel formulations provided herein are typically in the form ofa gel administered using a syringe (a paste could similarly be preparedand administered orally). A typical novel gel formulation thus containsmetamizole, water, and at least one (and typically two or more)pharmaceutically acceptable polymeric excipients that together with theformulation conditions used to prepare the gel, provide a gel of thedesired viscosity.

Suitable pharmaceutically acceptable polymeric excipients include, forexample and without limitation, albumin, acacia, alginic acid (oralginate salts, e.g. sodium alginate), bentonite, carbomers,carboxymethylcellulose, carrageenan, cellusoses, cellulose ethers,chitosan derivatives, dextran, divinyl ether-maleic anhydride (DIVEMA),dydroxyethylcellulose, ethylcellulose, gelatin, guar gum, hyaluronicacid (HA), hydroxyethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, methylcellulose, N-(2-Hydroxypropyl)methacrylamide (HPMA), magnesium aluminum silicate, methylcellulose,pectins, polyacrylamides, polyacrylic acid (PAA), polyethylene glycol(PEG) and PEG conjugates, polyethylene oxides, polyoxamers,polyoxazoline, polyphosphates, polyphosphazenes, polyvinyl alcohol(PVA), polyvinyl pyrrolidone (PVP), polyvinyl pyrrolidone-vinyl acetate(PVP-VA), starch or starch based derivatives, tragacanth, and xanthangum. Those of skill in the art will appreciate that these polymers mayvariously be called gelling agents or thickening agents in the art andthat any pharmaceutically acceptable gelling agent or thickening agentmay be used in a gel or paste formulation, including, in particular, assubstitutes for all or some portion of or in addition to the polymericexcipient(s) specifically exemplified in the illustrative novelembodiments of certain formulations described in the examples below.

In various embodiments, the oral pharmaceutical formulation containshydroxypropyl cellulose (HPC) and/or a paraben. In some suchembodiments, HPC may be present at a concentration of 10 to 50 mg/ml, or10 to 40 mg/ml, or 10 to 30 mg/ml, or 15 to 25 mg/ml. The sum of theparabens may, in some embodiments, be present at a concentration of 0.1to 5 mg/ml, or 0.5 to 5 mg/ml, or 1 to 3 mg/ml. Klucel™ HXF PH (AshlandChemical) is a commercially available hydroxypropyl cellulose, andmethyl paraben and propyl paraben are available commercially as well(Ruger Chemical).

In some embodiments, the oral formulation has from about 25% to at leastabout 50% metamizole; 0.5 to 10% of one or more thickening agents; andotherwise contains water and optionally other pharmaceuticallyacceptable excipients (including, without limitation, one or morepolymeric excipients, a preservative, such as an antioxidant, such assodium metabisulfite, and/or an antimicrobial agent, a buffer tomaintain the desired pH, and a flavoring).

A flavoring agent, when employed, may include any natural,nature-identical, and/or artificial flavoring substance(s) that altersthe flavor of the pharmaceutical composition to increase acceptance bythe intended equine recipient of the administered unit dose. In someembodiments, the pharmaceutical composition contains a flavoring agentin a range of 0.5% w/w to 10% w/w, of 1% w/w to 5% w/w, and preferablyof about 2% w/w. In some embodiments, the flavoring agent of thepharmaceutical composition is apple.

The pharmaceutical formulation may further include one or moreadditional excipients that improve the properties or function of theformulation. For example, in some embodiments the pharmaceuticalformulation contains one or more preservative agents. In someembodiments, the pharmaceutical formulation contains one or morepreservative agents selected from the group consisting of alcohol,benzyl alcohol, bronopol, chlorbutol, chlorocreson, a paraben such as,without limitation, butyl, methyl or propyl paraben, phenol,phenylethanol, sodium benzoate, potassium sorbate, sorbic acid,glycerin, and propylene glycol. In some embodiments, the pharmaceuticalcomposition contains a preservative agent in a range of 0.05% w/w to0.5% w/w, typically the amount is about 0.2% w/w. In some embodiments,the pharmaceutical composition contains at least two preservative agentssuch as methylparaben and propylparaben. In other embodiments, thepharmaceutical compositions contain a preservative that is anantioxidant, such as sodium metabisulfite. Various formulations providedherein include sodium metabisulfite, methylparaben, and propylparaben.

The pharmaceutical formulation provided herein may further comprise abuffering agent, such as a buffering salt and/or a pH bufferingadditive. In some embodiments, the pharmaceutical composition contains apreservative agent with solvent properties, such as propylene glycol, ata higher concentration, for example, at a concentration of 10 mg/ml to500 mg/ml, or 10 mg/ml to 300 mg/ml, or 50 mg/ml to 300 mg/ml, or 50mg/ml to 200 mg/ml, or 50 mg/ml to 150 mg/ml.

In some embodiments, the oral formulation provided herein comprises anaqueous solution, pH 7.5-8, comprising 250-750 mg/mL metamizole sodiummonohydrate, 5-15 mg/ml xanthan gum, and 50-150 mg/ml propylene glycol.In some embodiments, the oral formulation comprises 1-50 mg/ml, 1-30mg/ml, 5-30 mg/ml, 5-20 mg/ml, or 10-20 mg/ml benzyl alcohol.

In some embodiments, the oral formulation provided herein comprises anaqueous solution, pH 7.8, comprising 500 mg/mL metamizole sodiummonohydrate, 10 mg/ml xanthan gum, and 100 mg/ml propylene glycol. Insome embodiments, the formulation may comprise 15 mg/ml benzyl alcohol.

The present disclosure further relates to processes for preparing thenew pharmaceutical formulations provided herein. In some embodiments,the process for the preparation of the pharmaceutical formulationcomprises a first step of heating 30% of the water to between 60° C. and70° C., in a first container. The heated water in the first container isthen mixed at a high speed. Metamizole is then added to the heated waterand mixed until dissolved. The temperature of the mixture is thenreduced to between 50° C. and 60° C. A first preservative agent is thenadded to the mixture and mixed until dissolved, followed by the additionof a second preservative agent which is also mixed until dissolved. Aflavoring agent is then added to the mixture and mixed until fullyincorporated into the mixture. The gelling agent is then added tomixture and mixed for 5 minutes to create a slurry. In a separatecontainer, the remaining 70% of the water is maintained at a temperatureless than 21° C. and is mixed at low speed. The slurry from the firstcontainer is then added to the water of the second container and mixeduntil a gel forms.

In some embodiments, a thickening agent is added to at least one of thefirst and second containers prior to adding the slurry to the secondcontainer. In some embodiments, a thickening agent is added to thesecond container before and/or after the gel forms.

The oral gel pharmaceutical formulation provided herein may have theadvantage of physical properties that provide a composition that iseasily administered using a needle-less syringe to a horse, where thegel's viscosity helps retain the administered amount in the horse'smouth until it is swallowed. The novel pharmaceutical formulation hasthe further advantage of providing a unit dose form of metamizole(amount of gel administered) that is therapeutically effective to treatan equine for pyrexia.

The pharmaceutical compositions provided herein may have the advantageof assuring appropriately viscous formulations containingtherapeutically effective amounts of metamizole optionally incombination with a flavoring agent that increases tolerability to theequine subject intended for treatment. In various embodiments, thepresent disclosure provides gels that are stable for at least a day, aweek, two weeks, or at least 30 days in-use, e.g., at room temperatureand that are easily dosed and administered via needle-less syringe orother similarly facile mode of oral administration. In many embodiments,commercial products will comprise a container containing a plurality ofdoses (from about 3 to about 30, or about 3 to about 10, or about 3 toabout 6, for example and without limitation) of a pharmaceuticalcomposition provided herein, which products may be packaged and sold ina single container, whereby the user accesses and administers the dosesvia a syringe, which optionally may be packaged or sold with thepharmaceutical formulation. In some embodiments, the pharmaceuticalcomposition may be stored, for example, in its unopened container, forup to 1 year or up to 2 years, without significant loss of efficacy.

In one aspect, the present disclosure thus provides a method of treatingpyrexia in an equine comprising administering an oral formulation of atherapeutically effective dose of metamizole to an equine patient. Theformulation does not have to be novel; as illustrated in the examples,orally administered metamizole prepared for IV administration can beorally administered instead in accordance with the present disclosure.However, novel formulations are provided that may offer significantbenefit in administration and efficacy. While the unit dose forms usedin the methods provided herein may be administered at any frequency, andwhile in some embodiments a single dose will provide the desiredtreatment, the methods provided herein also include repeat dailyadministration, including up to at least 3 times daily for up to atleast 5 days. In various embodiments of these methods, thetherapeutically effective dose is 30-35 mg/kg, and the unit dose isadministered in a formulation in which metamizole is present at a w/wpercentage of at least 25% and typically at least 50% of theformulation, enabling a unit dose to be in the range of 20-50 ml.

EXAMPLES Example 1: Demonstration That Orally Administered MetamizoleCan Treat Pyrexia In Equines

A study in four horses was conducted to demonstrate oral bioavailabilityof metamizole. The commercially available Vetalgina product (Intervet)for IV administration (sodium salt) was administered in accordance withthe manufacturer's instructions. Plasma was collected prior toadministration and at specified intervals for up to 48 hours. Horsesunderwent a washout period, and then were administered the activeingredient (metamizole sodium monohydrate) in a water slurry to thehorses' stomach via nasogastric intubation. Plasma was collected againprior to intravenous administration and at specified intervals for up to48 hours. Horses were treated with matched doses on a milligram perkilogram basis for both test articles. Plasma was assayed for theprimary metabolite of metamizole sodium, 4-methylaminoantipyrine(4-MAA). The results demonstrated comparable bioavailability between theorally and parenterally administered metamizole, as shown in FIG. 1.

A second pilot study was conducted to demonstrate efficacy of orallyadministered metamizole. Metamizole, as an active ingredient, wasformulated into a simple gel for oral administration and dosed at 30mg/kg body weight. Eight horses with naturally occurring respiratoryinfections were provided. The temperatures of the horses were monitored.Horses selected for this study demonstrated a consistent temperature≥102.0° F. for 6 hours. Horses were treated up to three times with anoral formulation of metamizole sodium. Rectal temperature was monitoredto determine response to treatment. All 8 horses demonstrated aclinically significant improvement, as defined by a ≥2° F. decrease intemperature, or a return to normothermia (≤101.0° F.) 6 hours followingdose administration, in rectal temperature following oral administrationof metamizole sodium. Table 1 describes the findings for the first doseadministered. Pyrexia returned at timepoints appropriate for the drug'splasma residence time. This study demonstrated that oral administrationof metamizole sodium is effective in controlling fever in adult horses.

TABLE 1 Responder/Non-responder at Hour 6 Following the First DoseTreated Patients Patient ID Temperature at Hour 0 Temperature at Hour 6Response 706 103.5 101.0 Yes 711 102.2 98.6 Yes 712 102.7 100.8 Yes 713102.0 99.8 Yes 717 102.0 99.1 Yes 719 102.2 99.8 Yes 720 102.3 98.7 Yes722 103.9 101.1 Yes

Example 2: Oral Formulation of Metamizole

220 grams of purified water is placed into a first container and heatedto 60-70° C. while undergoing mixing at a high speed. 249 grams ofmetamizole sodium monohydrate is added to the heated water and mixeduntil completely dissolved. The temperature of the mixture is reduced to55-60° C. 1.8 grams of methyl paraben is added to the first containerand mixed until completely dissolved. 0.2 grams of propyl paraben isthen added to the first container and mixed until completely dissolved.20.4 grams of Klucel™ HXF PH hydroxypropylcellulose is then added to thefirst container and mixed for 5 minutes to create a slurry. 514 grams ofpurified water is then added to a second container and mixed at a lowspeed while maintaining the temperature of the purified water in thesecond container to below 22° C. The slurry from the first container isadded to the second container and mixed until a gel forms.

Two lots (one of about 1 kg and the other over 2 kg, with metamizolesodium monohydrate present in an amount of at least 244 mg/ml) weremanufactured generally in accordance with the above process, andaliquots placed in 200 cc amber bottles (˜140-160 ml per bottle) andstored at 40° C., 75% relative humidity for an initial assessment ofstability. After one month, both lots demonstrated greater than 94%label claim, with one lot at 99% label claim.

The oral formulation of metamizole was an aqueous formulation comprising249 mg/ml metamizole sodium monohydrate, 20.4 mg/ml Klucel™ HXF, 1.8mg/ml methyl paraben, and 0.2 mg/ml propyl paraben.

Example 3: Treatment of Pyrexia

A horse is treated for pyrexia with an oral gel formulation ofmetamizole sodium monohydrate at the dose of 35 mg/kg. For example, ahorse weighing 1000 lbs (454 kg) receives ˜16 g of metamizole sodiummonohydrate in a dose of about 30 ml, and the concentration of themetamizole in the dose is about 500 mg/ml.

In another instance, a horse is treated for pyrexia with an oral gelformulation of metamizole sodium monohydrate at a dose of 30 mg/kg. Invarious instances, horses are treated for pyrexia with an orallyadministered gel formulation of metamizole sodium monohydrate at a doseof 30-35 mg/kg, and the this dose is administered from once to no morethan up to 3 times daily, for one to up to 5 days.

Example 4: Treatment of Pyrexia with Oral Formulation of Metamizole

A two-phase study to determine the efficacy of oral metamizole in maturehorses was conducted as follows. In the first phase, 9 horses withclinical signs of infectious disease were enrolled. Once a horse had asingle temperature reading of ≥102.0° F., it was enrolled in the studyand dosed orally within 1 hour with metamizole sodium monohydrate at 30mg/kg.

In the second phase, 8 horses with clinical signs of infectious diseasewere enrolled. Once a horse had a single temperature reading of ≥102.0°F., it was enrolled in the study and dosed orally within 1 hour withmetamizole sodium monohydrate at 40 mg/kg.

The oral formulation of metamizole used for both phases was an aqueousformulation comprising 500 mg/ml metamizole sodium monohydrate, 10 mg/mlxanthan gum, and 100 mg/ml propylene glycol, and 15 mg/ml benzylalcohol. The formulation was adjusted to pH 7.8 using sodium hydroxide.

For both phases, rectal temperature was monitored at pre-determinedintervals. Horses were redosed based on rectal temperature and minimumdosing intervals up to five additional times, for a total of six doses.Fever was required for redose with metamizole. Primary responders weredefined as horses where the temperature at Hour 6 decreased either ≥2°F. from Hour 0 or decreased to ≤101.0° F. after Dose 1. Table 2 showsthe results of the study for all doses.

TABLE 2 Responder/Non-responder at Hour 6 Following All Doses Responseat 6 Hours post Dose Patient Treatment Dose Dose Dose Dose Dose Dose IDGroup 1 2 3 4 5 6 798 30 mg/kg N N Y Y ** Y 799 30 mg/kg Y Y Y 811 30mg/kg Y Y Y Y Y 813 30 mg/kg N  Y* Y Y Y Y 814 30 mg/kg Y  Y* Y N N Y815 30 mg/kg Y N Y N N Y 816 30 mg/kg Y Y N Y N N 817 30 mg/kg Y  Y* N NY 818 30 mg/kg Y Y Y  Y* Y 821 40 mg/kg Y 823 40 mg/kg N Y Y Y N Y 82440 mg/kg Y Y Y 826 40 mg/kg Y Y N Y Y N 827 40 mg/kg Y Y 829 40 mg/kg YY Y Y Y N 830 40 mg/kg Y Y 831 40 mg/kg Y Y Y Y *Patients with baselinetemperature less than 102° F. **Baseline temperature = 101.2° F.,therefore this visit was excluded from response status assessment

In phase 1 (30 mg/kg), 7/9 horses were defined as primary respondersafter Dose 1. In Phase 2 (40 mg/kg), ⅞ horses were defined as primaryresponders after Dose 1. Adverse events were consistent with theunderlying infections required for enrollment.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, the descriptions and examples should not be construed aslimiting the scope of the invention. The disclosures of all patent andscientific literature cited herein are expressly incorporated in theirentirety by reference.

1-24.(canceled)
 25. A pharmaceutical composition comprising 200 mg/ml to750 mg/ml metamizole, wherein the pharmaceutical composition is for oraladministration to equines.
 26. The pharmaceutical composition of claim25, wherein the pharmaceutical composition is a gel or paste.
 27. Thepharmaceutical composition of claim 25, wherein the concentration ofmetamizole in said pharmaceutical composition is from 400 mg/ml to 600mg/ml.
 28. The pharmaceutical composition of claim 25, wherein saidpharmaceutical composition comprises at least one polymeric excipient.29. The pharmaceutical composition of claim 28, wherein at least onepolymeric excipient is selected from albumin, acacia, alginic acid (oralginate salts, e.g. sodium alginate), bentonite, carbomers,carboxymethylcellulose, carrageenan, cellusoses, cellulose ethers,chitosan derivatives, dextran, divinyl ether-maleic anhydride (DIVEMA),dydroxyethylcellulose, ethylcellulose, gelatin, guar gum, hyaluronicacid (HA), hydroxyethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, methylcellulose, N-(2-Hydroxypropyl)methacrylamide (HPMA), magnesium aluminum silicate, methylcellulose,pectins, polyacrylamides, polyacrylic acid (PAA), polyethylene glycol(PEG) and PEG conjugates, polyethylene oxides, polyoxamers,polyoxazoline, polyphosphates, polyphosphazenes, polyvinyl alcohol(PVA), polyvinyl pyrrolidone (PVP), polyvinyl pyrrolidone-vinyl acetate(PVP-VA), starch or starch based derivatives, tragacanth, and xanthangum.
 30. (canceled)
 31. (canceled)
 32. The pharmaceutical composition ofclaim 25, wherein said pharmaceutical composition comprises at least onepreservative agent.
 33. The pharmaceutical composition of claim 32,wherein the preservative agent is selected from alcohol, benzyl alcohol,bronopol, chlorbutol, chlorocreson, a paraben, butyl paraben, methylparaben, propyl paraben, phenol, phenylethanol, sodium benzoate,potassium sorbate, sorbic acid, glycerin, and propylene glycol.
 34. Thepharmaceutical composition of claim 25, wherein said pharmaceuticalcomposition comprises at least one paraben.
 35. (canceled) 36.(canceled)
 37. (canceled)
 38. The pharmaceutical composition of claim25, wherein said pharmaceutical composition comprises xanthan gum. 39.The pharmaceutical composition of claim 38, wherein the xanthan gum ispresent at a concentration of 5 mg/ml to 20 mg/ml.
 40. Thepharmaceutical composition of claim 25, wherein said pharmaceuticalcomposition comprises propylene glycol.
 41. The pharmaceuticalcomposition of claim 40, wherein the propylene glycol is present at aconcentration of 50 mg/ml to 200 mg/ml.
 42. The pharmaceuticalcomposition of claim 25, wherein the composition comprises 500 mg/mLmetamizole sodium monohydrate, 10 mg/ml xanthan gum, and 100 mg/mlpropylene glycol, in an aqueous solution.
 43. (canceled)
 44. (canceled)45. The pharmaceutical composition of claim 25, wherein the metamizoleis metamizole sodium monohydrate.
 46. The pharmaceutical composition ofclaim 25, wherein the pharmaceutical composition has a viscosity of 200cps to 20,000 cps at 25° C.
 47. (canceled)
 48. (canceled)
 49. (canceled)50. The pharmaceutical composition of claim 25, wherein thepharmaceutical composition comprises benzyl alcohol.
 51. Thepharmaceutical composition of claim 50, wherein the benzyl alcohol ispresent at a concentration of 1-50 mg/ml.
 52. (canceled)
 53. Thepharmaceutical composition of claim 25, wherein the compositioncomprises metamizole at a concentration of 400 mg/ml to 600 mg/ml,xanthan gum at a concentration of 5 mg/ml to 20 mg/ml, and propyleneglycol at a concentration of 50 mg/ml to 200 mg/ml.